This K24 renewal application provides 33% salary effort for Dr. Hauser and supplements institutional support for his continued mentoring of MD and MD/PhD fellows and junior faculty and for expansion of his patient- oriented research program. A focus of the Hauser Lab is to identify biomarkers of Pseudomonas aeruginosa that define particularly aggressive strains. Past work has successfully identified several genes that are associated with more severe infections in mouse models. The goal of the proposed research is to expand these studies into populations of human patients. In the first project, the focus will be on acute respiratory infections. P. aeruginosa genes associated with strains that cause especially severe ventilator-associated pneumonia in intensive care unit patients will be identified. To begin to parse genes into functional categories, those genes that allow P. aeruginosa to resist killing by neutrophils will also be identified. In the second project, the focus will be on chronic respiratory infections. A systems biology approach will be used to identify P. aeruginosa strains capable of persisting in the airways of individuals with cystic fibrosis. A mouse model of chronic airway infection will then be used to determine whether aspects of these strains play a causal role in persistence. These projects combine powerful genomic, genetic, and microbiological techniques with human specimens and corresponding clinical data to yield cutting-edge patient-oriented research. They are thus ideal training vehicles for junior clinician investigators and have the potential to lead to improvements in patient care. Mentees will participate in a rigorous and broad mentoring program that utilizes the many resources available at Northwestern University to maximize their development into independent patient-oriented researchers. In summary, this K24 award will provide salary support and research funds to allow Dr. Hauser to spend a substantial portion of his effort mentoring clinical fellows and junior faculty in patient-oriented research and to expand his patient-oriented research program.